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Evolution
Human and mouse genomic sequences reveal extensive breakpoint reuse in mammalian evolution

Pavel Pevzner, and Glenn Tesler ^*

Department of Computer Science and Engineering, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0114

Edited by Michael S. Waterman, University of Southern California, Los Angeles, CA and approved May 5, 2003 (received for review January 21, 2003)

The human and mouse genomic sequences provide evidence for a larger number of rearrangements than previously thought and reveal extensive reuse of breakpoints from the same short fragile regions. Breakpoint clustering in regions implicated in cancer and infertility have been reported in previous studies; we report here on breakpoint clustering in chromosome evolution. This clustering reveals limitations of the widely accepted random breakage theory that has remained unchallenged since the mid-1980s. The genome rearrangement analysis of the human and mouse genomes implies the existence of a large number of very short "hidden" synteny blocks that were invisible in the comparative mapping data and ignored in the random breakage model. These blocks are defined by closely located breakpoints and are often hard to detect. Our results suggest a model of chromosome evolution that postulates that mammalian genomes are mosaics of fragile regions with high propensity for rearrangements and solid regions with low propensity for rearrangements.

A more accurate estimate for the number of breakpoints would involve the number of chromosomes in the common ancestor of human and mouse, which remains unknown. See refs. 32 and 33 for the analysis of chromosomal organization in the mammalian ancestor.

Similarly to Nadeau and Taylor (1), we represent the genome as a single interval rather than a set of intervals corresponding to chromosomes. We also estimate the number of breakpoints in breakpoint regions as n = N_b - N_c + N_r although some of these breakpoints may fall at the ends of chromosomes and, in this case, should not be counted. In addition, the exact borders of the syntenic blocks are not well defined and may extend into the breakpoint regions. However, these simplifications only slightly affect our analysis.

G is the total length of the draft human sequence, comprised of the synteny blocks (2,707 Mb), breakpoint regions (172.5 Mb) and chromosome ends.

^¶ For expository purposes, this estimate uses the average breakpoint region length rather than the distribution of breakpoint region lengths. The estimate needs to be revisited in the (rather unlikely) case that the chromosome ends and a small number of long breakpoint regions account for almost all breakpoint reuse events.

^* To whom correspondence should be addressed. E-mail: gptesler{at}cs.ucsd.edu.

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